Radiofrequency Ablation of the Renal Sympathetic Nerves as a Treatment for Uncontrolled Hypertension Form

500 EXCHANGE STREET, PROVIDENCE, RI 02903-2699 MEDICAL COVERAGE POLICY | 1 (401) 274-4848 WWW.BCBSRI.COM EFFECTIVE DATE: 08|01|2025 POLICY LAST REVIEWED: 04|02|2025 OVERVIEW Radiofrequency ablation (RFA) of the renal sympathetic nerves is thought to decrease both the afferent sympathetic signals from the kidney to the brain and the efferent signals from the brain to the kidney. This procedure decreases sympathetic activation, decreases vasoconstriction, and decreases activation of the renin- angiotensin system. Radiofrequency ablation of the renal sympathetic nerves may act as a nonpharmacologic treatment for hypertension and has been proposed as a treatment option for patients with uncontrolled hypertension despite the use of anti-hypertensive medications. MEDICAL CRITERIA Not applicable PRIOR AUTHORIZATION Not applicable POLICY STATEMENT Medicare Advantage Plans Radiofrequency ablation of the renal sympathetic nerves is considered not covered for the treatment of uncontrolled hypertension as the evidence is insufficient to determine that the technology results in an improvement in the net health outcome. Commercial Products Radiofrequency ablation of the renal sympathetic nerves is considered not medically necessary for the treatment of uncontrolled hypertension as the evidence is insufficient to determine that the technology results in an improvement in the net health outcome. COVERAGE Benefits may vary between groups/contracts. Please refer to the Evidence of Coverage or Subscriber Agreement for applicable not medically necessary/not covered surgery benefits/coverage. BACKGROUND Uncontrolled Hypertension Hypertension is estimated to affect approximately 30% of the population in the U.S. It accounts for a high burden of morbidity related to stroke, ischemic heart disease, kidney disease, and peripheral arterial disease. An estimated 1 in 4 adults with hypertension have their hypertension under control, but the remaining 77% (93million) remain uncontrolled. Uncontrolled hypertension is diagnosed when an individual's blood pressure remains above targeted levels when a patient either is not using, or unable to use, treatments to control blood pressure or when hypertension persists despite antihypertensive therapies. The definition of uncontrolled hypertension is inclusive of resistant hypertension in which blood pressure remains above the targeted range despite the use of 3 or more antihyperensive medications, including a diuretic, with complementary mechanisms of action. A number of factors may contribute to uncontrolled hypertension including nonadherence to medications, excessive salt intake, inadequate doses of medications, excess alcohol intake, volume overload, drug-induced hypertension, and other forms of secondary hypertension. Also, sometimes itis necessary to address comorbid conditions (ie, obstructive sleep apnea) to control blood pressure adequately. Medical Coverage Policy | Radiofrequency Ablation of the Renal Sympathetic Nerves as a Treatment for Uncontrolled Hypertension

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Treatment - Radiofrequency Denervation of the Renal Sympathetic Nerves Increased sympathetic nervous system activity has been linked to essential hypertension. Surgical sympathectomy has been shown to be effective in reducing blood pressure but is limited by the adverse events of surgery and was largely abandoned after effective medications for hypertension became available. The renal sympathetic nerves arise from the thoracic nerve roots and innervate the renal artery, the renal pelvis, and the renal parenchyma. Radiofrequency ablation (RFA) is thought to decrease both the afferent sympathetic signals from the kidney to the brain and the efferent signals from the brain to the kidney. This procedure decreases sympathetic activation, decreases vasoconstriction, and decreases activation of the renin- angiotensin system.

The procedure is performed percutaneously with access at the femoral artery. A flexible catheter is threaded into the renal artery, and a controlled energy source, most commonly low-power RF energy, is delivered to the arterial walls where the renal sympathetic nerves are located. Once adequate RF energy has been delivered to ablate the sympathetic nerves, the catheter is removed.

Regulatory Status No RFA devices have been approved by the U.S. Food and Drug Administration (FDA) for ablation of the renal sympathetic nerves as a treatment for hypertension. Several devices have been developed for this purpose and are in various stages of application for FDA approval.
• The Symplicity Spyral™ Renal Denervation System (Medtronic) is a multielectrode RFA catheter system designed to deliver 4-quadrant ablations. On August 23, 2023 the FDA Advisory Committee for Circulatory System Devices voted that the Symplicity Spyral system met its safety endpoint as well asits efficacy endpoint, but after a tied vote in which the chairperson cast the final vote, the committee determined that the device did not achieve a positive balance of benefits and harms. • The EnligHTN™ Multi-Electrode Renal Denervation System (St. Jude Medical) is an RFA catheter usinga 4-point multiablation basket design. In January 2014, the EnligHTN™ Renal Guiding Catheter was cleared for marketing by the FDA through the 510(k) process, based on substantial equivalence to predicate devices for the following indication: percutaneous use through an introducer sheath to facilitate a pathway to introduce interventional and diagnostic devices into the renal arterial vasculature. • The Vessix™ Renal Denervation System (Boston Scientific; formerly the V2 renal denervation system, Vessix Vascular) is a combination of an RF balloon catheter and bipolar RF generator technologies, intended to permit a lower voltage intervention.

Other RFA catheters (eg, Thermocouple Catheter™ [Biosense Webster]) used for other types of ablation procedures (eg, cardiac electrophysiology procedures) have been used off-label for RFA of the renal arteries. In 2020, the FDA granted breakthrough therapy designation to 2 renal artery denervation systems - SoniVie’s Therapeutic Intra-Vascular Ultrasound (TIVUS) System and Recor's Paradise Renal Denervation System – for the treatment of patients with persistently elevated blood pressure. However, ultrasound-based renal denervation systems are outside of the scope of this evidence review.

For individuals who have uncontrolled hypertension, despite the use of anti-hypertensive medications, who receive RFA of the renal sympathetic nerves, the evidence includes several RCTs, numerous systematic reviews of the RCTs, and a multinational registry study. Relevant outcomes are symptoms, change in disease status, morbid events, medication use, and treatment-related morbidity. The proof of principle SPYRAL HTN-OFF MED study found that multielectrode renal denervation was superior to sham in the absence of background antihypertensive medication therapy, with between-group differences of -4.0 mmHg for 24-h SBP and -6.6 for office SBP at 3 months. The unpowered SPYRAL HTN-ON MED Pilot study also found significant between-group differences of -7.4 mmHg for 24-h SBP and -6.8 mmHg for office SBP at 6 months; however, results were only significant for the subgroup of patients non-adherent to medications. Long-term data from the SPYRAL HTN-ON MED study suggest that blood pressure reductions with multielectrode renal denervation are progressive and sustained over time. The SPYRAL HTN-ON MED Expansion study failed to meet its primary efficacy endpoint and found only 0.03 mmHg difference between renal denervation and sham control groups at 6 months follow-up. A significant reduction in office blood

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pressure was noted at 6 months (-4.1mmHg). Confounding of these outcome estimates by unbalanced medication changes, missing 24-h SBP outcome data, and timing of antihypertensive medications related to 24-h SBP assessment may explain the discordant results between the pilot and expansion phases of this trial. Study interpretation is also complicated by short-term blinded follow-up and imputation of excluded crossover patient data. It is unclear which patients are most likely to derive benefit, and currently, there is no practical method to verify nerve destruction following ablation. Evidence from systematic reviews and meta- analyses are conflicting, but all available studies included evidence from both first and second-generation Symplicity catheters as well as multiple renal denervation methodologies such as ultrasound. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

CODING Medicare Advantage Plans The following CPT code(s) are considered not covered:
0338T Transcatheter renal sympathetic denervation, percutaneous approach including arterial puncture, selective catheter placement(s) renal artery(ies), fluoroscopy, contrast injection(s), intraprocedural roadmapping and radiological supervision and interpretation, including pressure gradient measurements, flush aortogram and diagnostic renal angiography when performed; unilateral 0339T Transcatheter renal sympathetic denervation, percutaneous approach including arterial puncture, selective catheter placement(s) renal artery(ies), fluoroscopy, contrast injection(s), intraprocedural roadmapping and radiological supervision and interpretation, including pressure gradient measurements, flush aortogram and diagnostic renal angiography when performed; bilateral

Commercial Products The following CPT code(s) are considered not medically necessary: 0338T Transcatheter renal sympathetic denervation, percutaneous approach including arterial puncture, selective catheter placement(s) renal artery(ies), fluoroscopy, contrast injection(s), intraprocedural roadmapping and radiological supervision and interpretation, including pressure gradient measurements, flush aortogram and diagnostic renal angiography when performed; unilateral 0339T Transcatheter renal sympathetic denervation, percutaneous approach including arterial puncture, selective catheter placement(s) renal artery(ies), fluoroscopy, contrast injection(s), intraprocedural roadmapping and radiological supervision and interpretation, including pressure gradient measurements, flush aortogram and diagnostic renal angiography when performed; bilateral

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PUBLISHED Provider Update, June 2025

REFERENCES

1. Acelajado MC, Calhoun DA. Resistant hypertension, secondary hypertension, and hypertensive crises: diagnostic evaluation and treatment. Cardiol Clin. Nov 2010; 28(4): 639-54. PMID 20937447
2. Centers for Disease Control and Prevention (CDC). Facts About Hypertension, Updated July 6, 2023; https://www.cdc.gov/bloodpressure/facts.htm. Accessed September 28, 2023
3. Food and Drug Administration (FDA) Circulatory System Devices Panel. FDA Executive Summary, Premarket Application (PMA) for Pxxxxxx Medtronic, Inc. Symplicity Spyral Renal Denervation System.2023; https://www.fda.gov/media/171411/download. Accessed August 24, 2023
4. Doumas M, Papademetriou V, Douma S, et al. Benefits from treatment and control of patients with resistant hypertension. Int J Hypertens. Dec 22 2010; 2011: 318549. PMID 21234402
5. Zile MR, Little WC. Effects of autonomic modulation: more than just blood pressure. J Am Coll Cardiol. Mar 06 2012; 59(10): 910-2. PMID 22381426
6. Townsend RR, Mahfoud F, Kandzari DE, et al. Catheter-based renal denervation in patients with uncontrolled hypertension in the absence of antihypertensive medications (SPYRAL HTN-OFF MED): a randomised, sham-controlled, proof-of-concept trial. Lancet. Nov 11 2017; 390(10108): 2160- 2170.PMID 28859944

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7. Böhm M, Kario K, Kandzari DE, et al. Efficacy of catheter-based renal denervation in the absence of antihypertensive medications (SPYRAL HTN-OFF MED Pivotal): a multicentre, randomised, sham- controlled trial. Lancet. May 02 2020; 395(10234): 1444-1451. PMID 32234534
8. Kandzari DE, Böhm M, Mahfoud F, et al. Effect of renal denervation on blood pressure in the presence of antihypertensive drugs: 6-month efficacy and safety results from the SPYRAL HTN-ON MED proof- of-concept randomised trial. Lancet. Jun 09 2018; 391(10137): 2346-2355. PMID 29803589
9. Mahfoud F, Kandzari DE, Kario K, et al. Long-term efficacy and safety of renal denervation in the presence of antihypertensive drugs (SPYRAL HTN-ON MED): a randomised, sham-controlled trial. Lancet. Apr 09 2022; 399(10333): 1401-1410. PMID 35390320
10. Kandzari DE, Kario K, Mahfoud F, et al. The SPYRAL HTN Global Clinical Trial Program: Rationale and design for studies of renal denervation in the absence (SPYRAL HTN OFF-MED) and presence(SPYRAL HTN ON-MED) of antihypertensive medications. Am Heart J. Jan 2016; 171(1): 82-
11. PMID 26699604
12. Coppolino G, Pisano A, Rivoli L, et al. Renal denervation for resistant hypertension. Cochrane Database Syst Rev. Feb 21 2017; 2(2): CD011499. PMID 28220472
13. Chen XH, Kim S, Zeng XX, et al. Account for Clinical Heterogeneity in Assessment of Catheter-based Renal Denervation among Resistant Hypertension Patients: Subgroup Meta-analysis. Chin Med J(Engl). Jul 05 2017; 130(13): 1586-1594. PMID 28639575
14. Silverwatch J, Marti KE, Phan MT, et al. Renal Denervation for Uncontrolled and Resistant Hypertension: Systematic Review and Network Meta-Analysis of Randomized Trials. J Clin Med. Feb 162021; 10(4). PMID 33669195
15. Ogoyama Y, Tada K, Abe M, et al. Effects of renal denervation on blood pressures in patients with hypertension: a systematic review and meta-analysis of randomized sham-controlled trials. Hypertens Res. Feb 2022; 45(2): 210-220. PMID 34657140
16. Pappaccogli M, Covella M, Berra E, et al. Effectiveness of Renal Denervation in Resistant Hypertension: A Meta-Analysis of 11 Controlled Studies. High Blood Press Cardiovasc Prev. Jun 2018;25(2): 167-176. PMID 29752703
17. Fadl Elmula FEM, Feng YM, Jacobs L, et al. Sham or no sham control: that is the question in trials of renal denervation for resistant hypertension. A systematic meta-analysis. Blood Press. Aug 2017; 26(4):195-203. PMID 28443356
18. Sun D, Li C, Li M, et al. Renal Denervation vs Pharmacotherapy for Resistant Hypertension: A Meta- Analysis. J Clin Hypertens (Greenwich). Aug 2016; 18(8): 733-40. PMID 26619813
19. Zhang X, Wu N, Yan W, et al. The effects of renal denervation on resistant hypertension patients: a meta-analysis. Blood Press Monit. Aug 2016; 21(4): 206-14. PMID 26901340
20. Yao Y, Zhang D, Qian J, et al. The effect of renal denervation on resistant hypertension: Meta-analysis of randomized controlled clinical trials. Clin Exp Hypertens. 2016; 38(3): 278-86. PMID 27018652
21. Fadl Elmula FE, Jin Y, Yang WY, et al. Meta-analysis of randomized controlled trials of renal denervation in treatment-resistant hypertension. Blood Press. 2015; 24(5): 263-74. PMID 26194721
22. Rosendorff C, Lackland DT, Allison M, et al. Treatment of hypertension in patients with coronary artery disease: a scientific statement from the American Heart Association, American College of Cardiology, and American Society of Hypertension. Circulation. May 12 2015; 131(19): e435-70. PMID 25829340
23. Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension. Jun 2018; 71(6): 1269-1324. PMID 29133354
24. Carey RM, Calhoun DA, Bakris GL, et al. Resistant Hypertension: Detection, Evaluation, and Management: A Scientific Statement From the American Heart Association. Hypertension. Nov 2018;72(5): e53-e90. PMID 30354828
25. James PA, Oparil S, Carter BL, et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA. Feb 05 2014; 311(5): 507-20. PMID 24352797
26. Mancia G, Kreutz R, Brunström M, et al. 2023 ESH Guidelines for the management of arterial hypertension The Task Force for the management of arterial hypertension of the European Society of

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Hypertension Endorsed by the International Society of Hypertension (ISH) and the European Renal Association (ERA). J Hypertens. Jun 21 2023. PMID 37345492

26. National Institute for Health and Care Excellence (NICE). Interventional procedures guidance: Percutaneous transluminal radiofrequency sympathetic denervation of the renal artery for resistant hypertension [IPG418]. March 2023; https://www.nice.org.uk/guidance/ipg754. Accessed August 29,

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